Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

The present invention provides a process for preparing a highly pure form
of malathion having a reduced level of toxic impurities. In addition, the
malathion prepared by the process of this invention is storage stable.
The level of toxic impurities in the malathion, e.g., isomalathion,
O,O,S-trimethyl phosphorodithioate (MeOOSPS), O,O,S-trimethyl
phosphorothioate (MeOOSPO), O,S,S-trimethyl phosphorodithioate (MeOSSPO),
malaoxon, isomalathion, diethyl fumarate, methyl malathion, dimethyl
malathion, O,O-methyl,ethyl-S-(1,2-dicarboethoxy)ethyl-phosphorodithioate
are lower than that of any other commercial preparation of malathion that
may be used for pharmaceutical purposes.

Claims:

1. A topical pharmaceutical formulation comprising at least 70% (w/w)
isopropyl alcohol, and terpineol, dipentene, pine needle oil, and
pharmaceutical grade malathion, said pharmaceutical grade malathion
containing 0.1% or less (w/w) MeOOSPO, 0.1% or less (w/w) MeOSSPO, 0.2%
or less (w/w) MeOOSPS, less than 0.1% (w/w) methyl malathion, 0.1% or
less (w/w) malaoxon and 0.1% or less (w/w) isomalathion.

2. The topical pharmaceutical formulation of claim 1, wherein the
pharmaceutical grade malathion has a purity greater than 98.5% (w/w).

3. The topical pharmaceutical formulation of claim 1, wherein the
pharmaceutical grade malathion has a purity of greater than 99% (w/w).

15. The topical pharmaceutical formulation of claim 1, wherein the amount
of isomalathion in the pharmaceutical grade malathion is not more than
0.1% (w/w), after storage for 3 months at 25.degree. C. and 60% relative
humidity.

18. The topical pharmaceutical formulation of claim 1, wherein the
pharmaceutical grade malathion contains less than 0.1% (w/w) MeOOSPO,
less than 0.1% (w/w) MeOSSPO, and less than 0.1% malathion carboxylic
acids.

[0005] Numerous impurities are found in malathion preparations; these
impurities include, O,O,S-trimethyl phosphorodithioate (MeOOSPS),
O,O,S-trimethyl phosphorothioate (MeOOSPO), O,S,S-trimethyl
phosphorodithioate (MeOSSPO), malaoxon, isomalathion, diethyl fumarate,
methyl malathion, dimethyl malathion,
O,O-methyl,ethyl-S-(1,2-dicarboethoxy)ethyl-phosphorodithioate, and
tetraethyl dithiodisuccinate (See, WHO Specifications and Evaluations for
Public Health Pesticides: Malathion, World Health Organization, 2003).
Some of these impurities are formed as breakdown products during storage,
but, the majority of these impurities are generated as unintentional
byproducts during synthesis. (Health Risk Assessment of Malathion
Coproducts in Malathion-Bait Used for Agricultural Pest Eradication in
Urban Areas, Report of the California Environmental Protection Agency,
1997). For example, during storage, malathion can convert to isomalathion
by dimerization, and the extent of isomerization is dependent on
particular storage conditions. (Health Risk Assessment of Malathion
Coproducts in Malathion-Bait Used for Agricultural Pest Eradication in
Urban Areas, Report of the California Environmental Protection Agency,
1997).

[0006] Storage of malathion at elevated temperatures, e.g., 40° C.,
significantly enhances toxicity of the malathion preparation (Umetsu et
al., J. Agric. Food Chem., 25:946-953 (1977)). In part, this enhancement
is due to an increase in isomalathion after storage. For example, after
storage for 6 months at 40° C., there was an increase in
isomalathion content from 0.2% to 0.45%, with an accompanying 35%
increase in toxicity as measured by LD50 in mice (Umetsu et al., J.
Agric. Food Chem., 25:946-953 (1977)). Because even small or trace
quantities of malathion impurities such as isomalathion have been shown
to be highly toxic, the presence of these impurities in any malathion
preparation, but especially one developed for pharmaceutical use, should
be reduced as much as possible. Moreover, given that malathion breaks
down into toxic by-products during storage, it is also desirable to
prepare malathion which is storage stable.

[0007] Many of these malathion impurities have been found to be toxic.
MeOOSPO and MeOSSPO can cause liver damage (Keadtisuke et al., Toxicology
Letters 52:35-46 (1990)), or immune suppression (Rodgers et al.,
Immunopharmacology 17:131-140 (1989)). Isomalathion has been shown to
cause death in people after spraying during insect eradication programs.
(Aldridge et al., Archives Toxicology 42:95-106 (1979)). The toxicity of
isomalathion is due to its ability to inhibit acetylcholinesterase; in
fact, isomalathion is approximately 1,000 times as active against
acetylcholinesterase as compared with malathion. (Berkman et al.
Synthesis of Chiral Malathion and Malathion, Tetrahedron Letters
33(11):1415-1418 (1992)).
O,O-methyl,ethyl-S-(1,2-dicarboethoxy)ethyl-phosphorodithioate,
isomalathion and MeOOSPO all exhibit pulmonary toxicity and can cause
death from hypoxia. (Imamura et al., Pharmacology and Therapeutics
38(3):419-427 (1988)). Malaoxon inhibits cholinesterase enzymes. (Umetsu
et al., J. Agric. Food Chem., 25:946-953 (1977)). Diethyl fumarate can
cause contact urticaria. (Maibach, Contact Dermatitis 12(3):139-140
(1985)). Malathion's physical properties make it difficult to remove
impurities by conventional means. For example, because malathion is a
liquid at ambient temperature (melting point=2.9° C.),
crystallization is difficult. Malathion also has a high boiling point
(156-157° C.), consequently, distillation also has its problems,
especially as malathion is unstable at elevated temperatures.

[0008] We have now developed a novel method for synthesizing and purifying
malathion for pharmaceutical use. The malathion prepared by the methods
of this invention has significantly lower levels of toxic impurities such
as isomalathion when compared with other, commercially available
malathion preparations that are currently used for pharmaceutical
purposes. Moreover, because malathion is known to be unstable, the levels
of toxic impurities, e.g., isomalathion, are known to increase over time,
there is a need to develop a stable form of malathion. The malathion of
the present invention is storage stable, i.e., even after storage at
elevated temperature and humidity, the levels of toxic impurities do not
increase significantly.

SUMMARY OF THE INVENTION

[0009] The methods of the invention provide for a process for preparing
malathion, comprising, the steps of (a) preparing a solution of
O,O-dimethyldithiophosphoric acid in an organic solvent, selected from
the group consisting of toluene, xylene and benzene; (b) extracting the
O,O-dimethyldithiophosphoric acid into water to generate an aqueous
solution of O,O-dimethyldithiophosphoric acid; (c) reacting the aqueous
solution of O,O-dimethyldithiophosphoric acid with diethyl maleate to
form malathion; and, (d) treating the malathion from step (c) with a
sulfur reagent, wherein the sulfur reagent has a pH less than about 7.0.
2. In one embodiment, the organic solvent is toluene.

[0010] The O,O-dimethyldithiophosphoric acid in step (a) may be prepared
by the steps comprising, the steps of: (i) adding phosphorous
pentasulfide (P2S5) to toluene to form a suspension; (ii)
heating the suspension to about 60° C.; (iii) adding methanol to
the suspension; (iv) stirring the suspension after addition of the
methanol for at least about 1 hour, while maintaining the temperature of
the suspension from about 55° C. to about 60° C.; (v)
filtering the suspension from step (iv) after cooling to about 18°
C. to about 25° C.; and, (vi) subjecting the suspension from step
(v) to vacuum distillation.

[0011] The malathion from step (d) may be isolated after treatment with
the sulfur reagent. The ratio of water to O,O-dimethyldithiophosphoric
acid in step (b) may be about 1:1 to about 10:1 (w/w). In one embodiment,
the ratio of water to O,O-dimethyldithiophosphoric acid is about 3:1
(w/w).

[0012] The solution of O,O-dimethyldithiophosphoric acid in step (a) may
be filtered before extraction into water in step (b). Alternatively, the
solution of O,O-dimethyldithiophosphoric acid in step (a) is distilled
before extraction into water in step (b).

[0013] In one embodiment, the molar ratio of diethyl maleate to
O,O-dimethyldithiophosphoric acid in step (c) is about 1:1 to about 2:1.
In another embodiment, the molar ratio of diethyl maleate to
O,O-dimethyldithiophosphoric acid in step (c) is about 1:1.

[0014] A polymerization inhibitor may be added to step (c) during the
reaction of the aqueous solution of O,O-dimethyldithiophosphoric acid
with the solution of diethyl maleate. The molar ratio of diethyl maleate
to the polymerization inhibitor may be about 50:1 to about 500:1. In one
embodiment, the molar ratio of diethyl maleate to polymerization
inhibitor is about 300:1. The polymerization inhibitor may be
hydroquinone.

[0015] The sulfur reagent is selected from the group consisting of alkali
metal bisulfites and alkaline earth metal bisulfites. In one embodiment,
the sulfur reagent is sodium bisulfite. In another embodiment, the sulfur
reagent comprises a 20% sodium bisulfite solution having a pH from about
6.1 to about 6.3. The malathion in step (d) may be treated with the 20%
sodium bisulfite solution for about 2 hours.

[0016] After treatment with the 20% sodium bisulfite solution, the
malathion may be washed with water, a 5% NaOH solution and at least two
more times with water. After washing with these solutions, the malathion
may be assayed for the presence of at least one impurity selected from
the group consisting of MeOOSPS, malaoxon, diethyl fumarate, dimethyl
malathion, methyl malathion, isomalathion and O,O-methyl, ethyl
S-(1,2-dicarboethoxy)ethyl phosphorodithioate, and combinations thereof.
In addition, the malathion is assayed for purity. If the malathion at
step contains greater than about 5.0% (w/w) diethyl fumarate, the washing
steps with water, NaOH and again with water may be repeated as discussed
above prior to isolating the malathion.

[0017] Preferably, the purified malathion contains 0.1% (w/w) or less of
tetraethyl dithiodisuccinate.

[0018] Preferably, the purified malathion contains 0.1% (w/w) or less of
diethyl fumarate. More preferably, the purified malathion contains 0.05%
(w/w) or less of diethyl fumarate.

[0019] At this stage of the purification, the malathion may be greater
than about 98.5% (w/w) malathion, less than about 5% (w/w) diethyl
fumarate and less than about 0.1% (w/w) isomalathion. In another
embodiment, the malathion may be greater than 98.5% (w/w) malathion, less
than about 0.2% (w/w) MeOOSPS, less than about 0.1% (w/w) malaoxon, less
than about 0.2% (w/w) diethyl fumarate, less than about 0.3% (w/w)
methylmalathion, and less than about 0.3% (w/w) O,O-methyl, ethyl
S-(1,2-dicarboethoxy)ethyl phosphorodithioate. In addition, there may be
less than about 0.1% (w/w) of any other detectable impurity in the
malathion at this stages of the purification.

[0020] The malathion prepared as above may be further purified by the
steps of: (l) adding water to the malathion; (m) subjecting the malathion
from step (k) to azeotropic distillation; (n) repeating steps (l) to (m)
at least one (l) time; and, (o) isolating the malathion. The ratio of
water to malathion in step (l) ranges from about 2:1 (w/w) to about 10:1
(w/w). In one embodiment, the ratio of water to malathion in step (l) is
about 3:1 (w/w). After azeotropic distillation, the malathion is assayed
for the presence of at least one impurity selected from the group
consisting of MeOOSPO, MeOSSPO, malaxon, MeOOSPS, diethyl fumarate,
dimethyl malathion, methyl malathion, O,O-methyl, ethyl
S-(1,2-dicarboethoxy)ethyl phosphorodithioate, tetraethyl
dithiosuccinate, isomalathion, malathion carboxylic acid,
mercaptosuccinate, tetraethyl thiodisuccinate and combinations thereof.
In addition, the malathion is assayed for purity. Steps (l) to (o) are
repeated if the malathion has greater than about 0.2% (w/w) MeOOSPS,
greater than about 0.1% (w/w) malaoxon, greater than about 0.2% (w/w)
diethyl fumarate, greater than about 0.2% (w/w) dimethylmalathion,
greater than about 0.3% (w/w) methylmalathion, greater than about 0.1%
(w/w) isomalathion, or there is less than about 98.5% (w/w) malathion.

[0021] Preferably, the purified malathion contains 0.2% (w/w) or less of
O,O,S-trimethyl phosphorodithioate. More preferably, the purified
malathion contains 0.1% (w/w) or less of O,O,S-trimethyl
phosphorodithioate.

[0022] At this stage of the purification, the malathion may have greater
than about 98.0% (w/w) malathion, less than about 0.1% (w/w) isomalathion
and less than about 0.1% (w/w) malathion monoacid. In one embodiment, the
isomalathion in this malathion preparation may be less than about 0.02%
(w/w). In a third embodiment, the malathion has greater than about 98.5%
(w/w) malathion, less than about 0.2% (w/w) MeOOSPS, less than about 0.1%
(w/w) malaoxon, less than about 0.2% (w/w) diethyl fumarate, less than
abut 0.2% (w/w) dimethylmalathion, less than about 0.3% (w/w)
methylmalathion and less than about 0.02% (w/w) isomalathion. In another
embodiment, the malathion has greater than about 99.5% (w/w) malathion,
less than about 0.1% (w/w) MeOOSPS, less than about 0.05% (w/w) malaoxon,
less than about 0.01% (w/w) diethyl fumarate, less than about 0.02% (w/w)
dimethylmalathion, less than about 0.07% (w/w) methylmalathion, and less
than about 0.02% (w/w) isomalathion. In any of the above embodiments,
there may be less than about 0.1% (w/w) of any other detectable impurity.

[0023] The malathion may be stored under a variety of different
conditions. After storage, the malathion is assayed for purity and for
the presence of various impurities. For example, after storage for about
3 months at about 5° C., the malathion is greater than about 98.0%
(w/w) malathion and less than about 0.03% (w/w) isomalathion. After
storage for at least about 3 months at about 25° C. and about 60%
relative humidity, the malathion may have greater than about 98.0% (w/w)
malathion and less than about 0.04% (w/w) isomalathion. After storage for
at least about 3 months at about 30° C. and about 60% relative
humidity, the malathion may have greater than about 98.0% (w/w) malathion
and less than about 0.06% (w/w) isomalathion. After storage for at least
about 3 months at about 40° C. and about 75% relative humidity,
the malathion may have greater than about 98.0% (w/w) malathion and less
than about 0.1% (w/w) isomalathion.

[0024] Malathion containing greater than about 98.0% (w/w) malathion, less
than about 0.1% (w/w) isomalathion and less than about 0.1% (w/w)
malathion monoacid may be formulated into a pharmaceutical formulation
comprising, at least about 0.5% (w/w) malathion and at least about 70%
(w/w) isopropyl alcohol. After storage at about 40° C. and about
75% relative humidity for about 3 months, the isomalathion present in the
formulation is less than about 0.07% (w/w). The pharmaceutical
formulation may further comprise at least about 12% (w/w) terpineol, at
least about 10% dipentene and at least about 0.28% pine needle alcohol.

[0025] The malathion prepared by the process of the invention comprises
the following embodiments: (i) greater than about 98.5% (w/w) malathion,
less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO,
less than about 0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion
carboxylic acid and less than about 0.1% (w/w) isomalathion; (ii) greater
than about 98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO,
less than about 0.1% (w/w) MeOSSPO, less than about 0.2% (w/w) MeOOSPS,
less than about 0.3% (w/w) malathion carboxylic acid and less than about
0.02% (w/w) isomalathion; (iii) greater than about 99.0% (w/w) malathion,
less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO
and less than about 0.1% (w/w) MeOSSPS, 0.03% (w/w) malathion carboxylic
acids and less than about 0.02% (w/w) isomalathion; and, (iv) greater
than about 99.0% (w/w) malathion, less than about 0.04% (w/w) MeOOSPO,
less than about 0.02% (w/w) MeOSSPO and less than about 0.1% (w/w)
MeOSSPS, 0.03% (w/w) malathion carboxylic acids and less than about 0.02%
(w/w) isomalathion.

[0026] The malathion prepared by the process of this invention is stable
after storage. Specifically, after storage at 5° C. for 3 months
the amount of isomalathion is not more than about 0.1% (w/w). After
storage for 3 months at 25° C. and 60% relative humidity, the
amount of isomalathion is not more than about 0.1% (w/w). After storage
for 3 months at 30° C. and 60% relative humidity, the amount of
isomalathion is not more than about 0.1% (w/w).

[0027] The present invention further provides a process for preparing
pharmaceutical grade malathion, comprising the steps of: [0028] (a)
reacting a phosphorus sulfide with methanol in an organic solvent to form
an organic solution of O,O-dimethyldithiophosphoric acid; [0029] (b)
extracting O,O-dimethyldithiophosphoric acid from the organic solution
into water to form an aqueous solution of O,O-dimethyldithiophosphoric
acid; [0030] (c) reacting the aqueous solution of
O,O-dimethyldithiophosphoric acid with diethyl maleate to form malathion;
[0031] (d) preparing an acidic aqueous solution containing at least one
sulfur reagent selected from the group consisting of bisulfites,
sulfites, and sulfides; [0032] (e) contacting the malathion with the
acidic aqueous solution at a pH below 7; [0033] (f) mixing the malathion
with water; and [0034] (g) distilling water from the mixture at a
temperature of about 60° C. or lower.

[0035] Preferably, the process further comprises after step (a) and before
step (b) the steps of:

[0036] (i) filtering the organic solution of O,O-dimethyldithiophosphoric
acid; and

[0038] The present invention further provides a composition of
pharmaceutical grade malathion, which contains 0.1% (w/w) or less of
isomalathion, and 0.1% (w/w) or less of each individual unknown impurity
present in the composition.

[0039] Preferably, the composition contains 0.05% (w/w) or less of
isomalathion. More preferably, the composition contains 0.02% (w/w) or
less of isomalathion.

[0040] Preferably, the composition contains less than 0.05% (w/w) of
O,O,S-trimethyl phosphorothioate (MeOOSPO). More preferably, the
composition contains less than 0.04% (w/w) of O,O,S-trimethyl
phosphorothioate (MeOOSPO).

[0041] Preferably, the composition contains less than 0.1% (w/w) of methyl
malathion. More preferably, the composition contains 0.08% (w/w) or less
of methyl malathion. More preferably, the composition contains 0.06%
(w/w) or less of methyl malathion.

[0042] Preferably, the composition contains less than 0.05% (w/w) of
O,O,S-trimethyl phosphorothioate (MeOOSPO) and less than 0.1% (w/w) of
methyl malathion. Preferably, the composition contains 0.05% (w/w) or
less of isomalathion, less than 0.04% (w/w) of O,O,S-trimethyl
phosphorothioate (MeOOSPO), and 0.08% (w/w) or less of methyl malathion.
Preferably, the composition contains 0.02% (w/w) or less of isomalathion,
less than 0.04% (w/w) of O,O,S-trimethyl phosphorothioate (MeOOSPO), and
0.06% (w/w) or less of methyl malathion.

[0043] The present invention further provides a commercial scale
composition of pharmaceutical grade malathion, which contains 0.1% (w/w)
or less of isomalathion, and 0.1% (w/w) or less of each individual
unknown impurity present in the composition.

[0044] Preferably, the commercial scale composition contains 0.05% (w/w)
or less of isomalathion. More preferably, the commercial scale
composition contains 0.02% (w/w) or less of isomalathion.

[0045] Preferably, the commercial scale composition contains less than
0.05% (w/w) of O,O,S-trimethyl phosphorothioate (MeOOSPO). More
preferably, the commercial scale composition contains less than 0.04%
(w/w) of O,O,S-trimethyl phosphorothioate (MeOOSPO).

[0046] Preferably, the commercial scale composition contains less than
0.1% (w/w) of methyl malathion. More preferably, the commercial scale
composition contains 0.08% (w/w) or less of methyl malathion. More
preferably, the commercial scale composition contains 0.06% (w/w) or less
of methyl malathion.

[0047] Preferably, the commercial scale composition contains less than
0.05% (w/w) of O,O,S-trimethyl phosphorothioate (MeOOSPO) and less than
0.1% (w/w) of methyl malathion. Preferably, the commercial scale
composition contains 0.05% (w/w) or less of isomalathion, less than 0.04%
(w/w) of O,O,S-trimethyl phosphorothioate (MeOOSPO), and 0.08% (w/w) or
less of methyl malathion. Preferably, the commercial scale composition
contains 0.02% (w/w) or less of isomalathion, less than 0.04% (w/w) of
O,O,S-trimethyl phosphorothioate (MeOOSPO), and 0.06% (w/w) or less of
methyl malathion.

[0048] The present invention further provides a commercial scale
composition of pharmaceutical grade malathion, which contains 0.1% (w/w)
or less of isomalathion after storing the composition for three (3)
months at 25° C.±2° C. and 60%±5% relative humidity.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention provides a process for preparing a highly
purified form of malathion that may be used for pharmaceutical
formulations. Malathion is synthesized by (a) preparing a solution of
O,O-dimethyldithiophosphoric acid in an organic solvent; (b) extracting
the O,O-dimethyldithiophosphoric acid into water to generate an aqueous
solution of O,O-dimethyldithiophosphoric acid; (c) reacting the aqueous
solution of O,O-dimethyldithiophosphoric acid with diethyl maleate to
form malathion; and, (d) treating the malathion from step (c) with a
sulfur reagent, wherein the sulfur reagent has a pH less than about 7.0.

[0050] The O,O-dimethyldithiophosphoric acid in step (a) may be produced
by (i) suspending phosphorus sulfide in an organic solvent, (ii) adding
methanol to the phosphorous sulfide suspension drop-wise and, (iii)
mixing the phosphorous sulfide suspension. A phosphorus sulfide is a
compound of formula PxSy, wherein x and y are integers.
Examples of phosphorus sulfides include compounds such as phosphorus
pentasulfide (P2S5), tetraphosphorus heptasulfide
(P4S7) as well as mixtures of these compounds. Phosphorus
pentasulfide is usually found as a dimer, tetraphosphorus decasulfide
(P4S10) (the term phosphorus pentasulfide includes, the dimer,
tetraphosphorus decasulfide). In one embodiment, the phosphorus sulfide
is phosphorus pentasulfide. Any suitable organic solvent may be used to
suspend the phosphorus sulfide. Suitable organic solvents such as
toluene, xylene and benzene as well as mixtures may be used. In a
preferred embodiment, toluene is used as the organic solvent for
suspending the phosphorous sulfide.

[0051] Because higher temperatures cause decomposition of
O,O-dimethyldithiophosphoric acid as well as formation of undesirable
byproducts, the temperature of the step where the phosphorous sulfide
suspension is mixed (step (iii), above) is controlled. Mixing may proceed
for approximately 1 hour, while maintaining the temperature of the
reaction vessel between about 55° C. to about 65° C. with
nitrogen (N2) bubbling. After mixing, the reaction mixture is cooled
to a temperature of about 18° C. to about 25° C.

[0052] Prior to extraction into water, the solution of
O,O-dimethyldithiophosphoric acid in an organic solvent may be further
purified by filtration, distillation or evaporation. Filtration removes
insoluble impurities such as any un-reacted solids, e.g., P2S5.
Other suitable methods of removing insoluble impurities, include,
decantation and centrifugation.

[0053] The solution of O,O-dimethyldithiophosphoric acid in the organic
solvent may be concentrated or purified by distillation. Preferably, the
solution of O,O-dimethyldithiophosphoric acid in the organic solvent is
distilled by azeotropic distillation. An advantage of distillation (e.g.,
azeotropic distillation) is that it effectively removes MeOOSPS without
generating the isomerization products of malathion and isomalathion.
Distillation may be performed under vacuum. Distillation removes volatile
impurities such as, hydrogen sulfide (H2S) as well as any unreacted
methanol or other organic solvents, e.g., toluene. If hydrogen sulfide is
present in the O,O-dimethyldithiophosphoric acid, it can react with
diethyl maleate or diethyl fumarate to form diethyl 2-mercaptosuccinate.
Diethyl 2-mercaptosuccinate can be oxidized to form a dimeric impurity,
tetraethyl dithiodisuccinate, which is very difficult to remove from any
malathion preparation.

[0054] Another advantage of the distillation (e.g., azeotropic
distillation) is to effectively remove unreacted methanol. If unreacted
methanol is present as an impurity in the O,O-dimethyldithiophosphoric
acid, it can react with malathion to form both methanolysis and
transesterification impurities. Methanolysis impurities include,
O,O,O,-trimethylthiophosphoric acid (MeOOOPS) and
O,O,S-trimethylthiophosphoric acid (MeOOSPO). Transesterification
impurities include, [(dimethoxyphosphinothioyl)thio]butanedioic acid
dimethyl ester (dimethyl malathion),
1-carboethoxy-2-carbomethoxy-1-[(dimethoxyphosphinothioyl)thio]ethane,
and 2-carboethoxy-1-carbomethoxy-1-[(dimethoxyphosphinothioyl)thio]ethane-
; 1-carboethoxy-2-carbomethoxy-1-[(dimethoxyphosphinothioyl)thio]ethane,
and 2-carboethoxy-1-carbomethoxy-1-[(dimethoxyphosphinothioyl)thio]ethane
are collectively referred to as methyl malathion. These impurities are
difficult to remove from the malathion preparation.

[0055] Another advantage of the distillation process is to remove
dissolved H2S. If H2S is present, it will react with diethyl
maleate to afford diethyl 2-mercaptosuccinate and dimerize to form
tetraethyl dithiodisuccinate.

[0056] Typically, the distillation step removes a portion of the organic
solvent, e.g., toluene xylene or benzene, together with other volatile
impurities such as methanol. After distillation, the concentration of the
O,O-dimethyldithiophosphoric acid in the solution is about 30% (w/w) to
about 70% (w/w); more preferably, the concentration of the
O,O-dimethyldithiophosphoric acid in solution may be about 50% (w/w).
Preferably, the distillation may be performed at reduced pressure, e.g.,
less than about 1 atmosphere (1 atmosphere=760 mm Hg). In another
embodiment, the distillation may be performed at a pressure of about 0.5
atmosphere, while in a third embodiment, the distillation may be
performed at a pressure of about 0.2 atmosphere.

[0057] After the distillation, evaporation or filtration step, the
O,O-dimethyldithiophosphoric acid in the organic solvent is extracted
into water to yield an aqueous solution of O,O-dimethyldithiophosphoric
acid. An advantage of the present invention is that extraction of the
O,O-dimethyldithiophosphoric acid into water significantly removes
MeOOSPS. Analysis by gas chromatography of the
O,O-dimethyldithiophosphoric acid in the organic solvent before
extraction with the water indicates that the O,O-dimethyldithiophosphoric
acid is contaminated with up to about 25-30% (w/w) of O,O,S-trimethyl
phosphorodithioate (MeOOSPS) as well as with other impurities, such as,
O,O,S-trimethyl phosphorothioate (MeOOSPO). After extraction with water,
gas chromatography analysis indicates that the quantity of
O,O,S-trimethyl phosphorodithioate (MeOOSPS) in the aqueous solution of
O,O-dimethyldithiophosphoric acid is reduced to about 5-6% (w/w) or less.

[0058] Any suitable quantity of water may be used for the extraction. The
ratio of water to the organic solution of O,O-dimethyldithiophosphoric
acid may be from about 1:1 to about 10:1 (w/w); preferably, the ratio is
about 3:1 (w/w). More preferably, the ratio of the solution of
O,O-dimethyldithiophosphoric acid in the organic solvent to water may be
about 1:1. Mixing of the water and the solution of
O,O-dimethyldithiophosphoric acid in the organic solvent produces a
reaction mixture containing two layers, an organic and an aqueous layer.
After separation of the organic and aqueous layers, the aqueous layer
which now contains the O,O-dimethyldithiophosphoric acid may be washed
with toluene. The aqueous solution of O,O-dimethyldithiophosphoric acid
is then reacted with a diethyl maleate to form malathion. Diethyl
fumarate may also be used in the reaction with the aqueous solution of
O,O-dimethyldithiophosphoric acid to form malathion. Because diethyl
maleate is not miscible with an aqueous solvent such as water, the
reaction is performed as a heterogeneous, two layer mixture containing an
aqueous layer (the aqueous solution of O,O-dimethyldithiophosphoric acid)
and organic layer (diethyl maleate or diethyl fumarate). The two-phase
mixture is subjected to mechanical mixing. Malathion collects in the
lower or organic phase. The above reaction is done by direct addition of
diethyl maleate to the aqueous solution of O,O-dimethyldithiophosphoric
acid. An advantage of the present invention is that there is no need to
isolate the O,O-dimethyldithiophosphoric acid in a concentrated form.
O,O-dimethyldithiophosphoric acid is poisonous, thus, direct addition
avoids the need to isolate any toxic compounds during the formation of
malathion.

[0059] In order to maximize the yield and purity of the malathion, the
conditions for reacting the aqueous solution of
O,O-dimethyldithiophosphoric with the diethyl maleate, e.g., reaction
temperature, reaction time, reagent ratio, may be optimized by those of
ordinary skill in the art. In one embodiment, the molar ratio of diethyl
maleate to O,O-dimethyldithiophosphoric acid may be from about 1:1 to
about 2:1. The reaction temperature may range from about 25° C. to
about 70° C.; more preferably, the reaction temperature is about
40° C. to about 65° C.; still more preferably, the reaction
temperature is about 53° C. The reaction time may vary, e.g., (i)
from about two (2) to about twelve (12) hours, (ii) from about five (5)
to about ten (10) hours, or, (iii) about eight (8) hours. The reaction
may be performed under a N2 atmosphere. After completion of the
reaction, the two solutions, the aqueous solution of
O,O-dimethyldithiophosphoric and the diethyl maleate, are cooled to about
18° C. to about 25° C. temperature, the solutions separated
and the diethyl maleate which contains the malathion washed at least two
more times with water.

[0060] Diethyl fumarate may be formed during the reaction of the aqueous
solution of O,O-dimethyldithiophosphoric acid with diethyl maleate. In
order to decrease polymerization of diethyl maleate and diethyl fumarate,
the reaction may be performed in the presence of a polymerization
inhibitor. Suitable polymerization inhibitors include hydroquinone. The
molar ratio of diethyl maleate to polymerization inhibitor is about 50:1
to about 500:1. For example, in one embodiment, the molar ratio of
diethyl maleate to polymerization inhibitor is about 300:1.

[0061] In order to further purify the malathion, the diethyl maleate
containing the malathion may be treated with a sulfur solution. The
inventors of the present invention surprisingly found that a sulfur
solution with a pH of less than about 7 is effective to eliminate dimer
impurity formation. The pH of the sulfur solution ranges from about 6.0
to about 7.0. The sulfur solution may be for example, a (i) bisulfite,
such as, sodium bisulfite, sodium metabisulfite, magnesium bisulfite or
ammonium bisulfite, (ii) sulfite, such as, sodium sulfite, potassium
sulfite, magnesium sulfite or ammonium sulfite, or (iii) sulfide such as,
sodium sulfide, potassium sulfide, calcium sulfide, ammonium sulfide or
ammonium bisulfide. The acidic, aqueous sulfur solution may be prepared
in any suitable manner (note, an aqueous solution of a bisulfite is
inherently acidic); suitable methods for preparing an acidic aqueous
solution of a bisulfite include dissolving a bisulfite in water. Aqueous
solutions of sulfites or sulfides are inherently basic. Therefore, an
acidic, aqueous solution of a sulfite or sulfide may be prepared by
dissolving a sulfite in water, followed by addition of an acid, such as,
hydrochloric acid or sulfuric acid, to reduce the pH below 7.0. An
advantage of the acidic sulfur solution is that it effectively increases
the purity of malathion. The importance of using an acidic sulfur
solution to further purify the malathion was demonstrated by the fact
that if the malathion was treated with a basic solution (i.e., pH>7.0)
of sulfites or sulfides, the resulting malathion was found to be
contaminated with greater than 0.2% (w/w) tetraethyl dithiodisuccinate.
In contrast, if the pH of the aqueous, sulfur solution was acidic, i.e.,
pH below 7.0, the malathion formed contained less than 0.2% (w/w)
tetraethyl dithiodisuccinate. At pH 7-12, treatment of malathion with
sulfur solution may also cause formation of tetraethyl thiodisuccinate
impurity. An additional advantage of using acidic sulfur solution is to
avoid malathion decomposition, which is known to occur more likely at a
basic pH (i.e., pH>7). (See, e.g., Cotham W E Jr., et al. Food Chem.
37:824-828 (1989)).

[0062] In one embodiment, the diethyl maleate, which contains the
malathion, is treated with a 20% (w/w) solution of sodium bisulfite (pH
from about 6.1 to about 6:3). After mixing the diethyl maleate with the
20% (w/w) sodium bisulfite solution at about 60° C. for about 2
hours, the mixture containing the two solutions, diethyl maleate and 20%
(w/w) sodium bisulfite, is cooled to about 18° C. to about
25° C. and the two solutions are then separated. The diethyl
maleate is then washed with water and the two solutions, the diethyl
maleate and water, separated; the diethyl maleate is then washed with a
5% (w/w) NaOH and the solutions separated. After washing with the NaOH,
the diethyl maleate may be washed at least two (2) more times with water
as described above.

[0063] At this stage of the purification, the purity of the malathion may
be assayed by high pressure liquid chromatography (HPLC). Other
techniques for assaying the purity of malathion and for determining the
presence of impurities include, gas chromatography (GC), and nuclear
magnetic resonance (NMR) spectroscopy (WHO Specifications and Evaluations
for Public Health Pesticides: Malathion, World Health Organization,
2003). Using these analytical techniques, the presence of the following
impurities may be determined, MeOOSPS, malaoxon, diethyl fumarate,
dimethyl malathion, methyl malathion, isomalathion, O,O-methyl, ethyl
S-(1,2-dicarboethoxy)ethyl phosphorodithioate, O,O-methyl, ethyl
S-(1,2-dicarboethoxy)ethyl phosphorodithioate; in addition, the presence
of any other detectable impurity may be determined using this
methodology.

[0064] If the malathion contains greater than 5% (w/w) diethyl fumarate,
the malathion is reprocessed by treating it again with the sulfur
solution (pH 6.0-7.0), 5% (w/w) NaOH and water, sequentially, as
described above. After reprocessing, the resulting malathion is assayed
by HPLC for both the purity of malathion and for the presence of any of
the impurities listed above.

[0065] At this stage of the purification, the malathion may exhibit the
following purity/impurity profile: (i) greater than about 98.5% (w/w)
malathion; (ii) less than about 5.0% (w/w) diethyl fumarate, and (iii)
less than about 0.1% (w/w) isomalathion. In a preferred embodiment, the
malathion may have the following purity/impurity profile: (i) greater
than about 98.5% (w/w) malathion, (ii) less than about 0.2% (w/w)
MeOOSPS, (iii) less than about 0.1% (w/w) malaoxon, (iv) less than about
0.2% (w/w) diethyl fumarate, (v) less than about 0.3% (w/w)
methylmalathion, (vi) less than about 0.1% (w/w) isomalathion, and (vii)
less than about 0.3% (w/w) O,O-methyl, ethyl S-(1,2-dicarboethoxy)ethyl
phosphorodithioate. In addition, at this stage of the purification, there
is not more than about 0.1% (w/w) of any other detectable impurity
present in the malathion.

[0066] In order to reduce the levels of impurities further, the malathion
prepared by the above process or malathion obtained from another
synthetic route may be further purified by the distillation with water.
Water is added to the malathion and the mixture subjected to azeotropic
distillation. An advantage of this azeotropic distillation process is
that it effectively removes MeOOSPS without producing the isomerization
product of malathion (i.e., isomalathion). Additionally, azeotropic
distillation is a more simple process as compared to air stripping or
flash distillation. It is also much more effective in removing MeOOSPS.
In one embodiment, the ratio of water to malathion is 3:1 (w/w). After
the first distillation is completed, water is added, and azeotropic
distillation repeated at least one more time. Again, the ratio of water
to malathion at this stage in the purification may be about 3:1 (w/w). As
long as there is a comparative excess of water present, the ratio of
water to malathion may range from about 2:1 to greater than about 10:1
(w/w). After these additional purification steps, addition of water
followed by azeotropic distillation, the purity of the malathion is
determined by HPLC. The impurities assayed for can include, MeOOSPS,
malaoxon, diethyl fumarate, dimethylmalathion, methylmalathion,
isomalathion, malathion carboxylic acids as well as any other detectable
impurity. If (i) MeOOSPS is greater than about 0.2% (w/w), (ii) malaxon
is greater than about 0.1% (w/w), (iii) diethyl fumarate is greater than
about 0.2% (w/w), (iv) dimethylmalathion is greater than about 0.2%
(w/w), (v) methylmalathion is greater than about 0.3% (w/w), (vi)
isomalathion is greater than about 0.1% (w/w), (vii) any other individual
detectable impurity is greater than 0.1% (w/w), or (viii) the malathion
is less than about 98.5% (w/w), then, additional water is added to the
malathion and azeotropic distillation repeated as described above. The
purity/impurity profile of the malathion is then assayed a second time.
Azeotropic distillation with the addition of water may be repeated until
the purity/impurity profile the wet malathion conforms to the criteria
set forth above for the purity of the malathion and for the % (w/w) of
various impurities.

[0067] At this stage of the purification, the malathion may have the
following purity/impurity profile:

(i) greater than about 98.5% (w/w) malathion; (ii) less than about 0.2%
(w/w) MeOOSPS; (iii) less than about 0.1% (w/w) malaxon; (iv) less than
about 0.2% (w/w) diethyl fumarate; (v) less than about 0.2% (w/w)
dimethylmalathion; (vi) less than about 0.3% (w/w) methylmalathion; or,
(vii) less than about 0.1% (w/w) isomalathion.

[0068] In another embodiment, the purity/impurity profile of malathion is:
(i) greater than about 98.5% (w/w) malathion; (ii) less than about 0.2%
(w/w) MeOOSPS; (iii) less than about 0.1% (w/w) malaoxon; (iv) less than
about 0.2% (w/w) diethyl fumarate; (v) less than abut 0.2% (w/w)
dimethylmalathion; (vi) less than about 0.3% (w/w) methylmalathion; (vii)
less, than about 0.1% (w/w) isomalathion; and, (viii) less than 0.1%
(w/w) any other detectable impurity.

[0069] In a third embodiment, the purity/impurity profile is: (i)
malathion greater than about 99.5% (w/w), (ii) about 0.1% (w/w) MeOOSPS,
(iii) less than about 0.05% (w/w) malaoxon, (iii) less than about 0.01%
(w/w) diethyl fumarate, (iv) less than about 0.02% dimethylmalathion, (v)
about 0.06% (w/w) methylmalathion, and, (vi) 0.07% (w/w) isomalathion.

[0070] Malathion free of water may be obtained by heating the malathion
after addition of water, followed by azeotropic distillation at a
temperature from about 35° C. to about 45° C., together
with air bubbling through the wet mass. The water content may be
monitored by the Karl Fisher procedure. United States Pharmacopeia
<921>. When the water content is reduced to not more than 0.1%
(w/w), the malathion is cooled and filtered to remove any foreign
particles. Filtration may be through glass paper.

[0071] After drying, the malathion is assayed by HPLC for the purity of
malathion as well as for the presence of various impurities, including,
MeOOSPO, MeOSSPO, malaxon, MeOOSPS, diethyl fumarate, dimethyl malathion,
methyl malathion, O,O-methyl, ethyl S-(1,2-dicarboethoxy)ethyl
phosphorodithioate, tetraethyl dithiosuccinate, isomalathion, malathion
carboxylic acids such as O,O-dimethyl-S-(1-carboxy-2-carboxyethoxy) ethyl
phosphorodithioate or O,O-dimethyl-S-(1-carboxy-2-carboxy) ethyl
phosphorodithioate), mercaptosuccinate and tetraethyl thiodisuccinate.
The HPLC assay of impurities may include all or only some of the
impurities selected from the above list of impurities. In addition, the
malathion may also be assayed for the presence of any other detectable
impurities.

[0072] Various embodiments of malathion are encompassed by the invention
including: (i) greater than about 98.5% (w/w) malathion, less than about
0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about
0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion carboxylic acid
and/or less than about 0.1% (w/w) isomalathion; (ii) greater than about
98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than
about 0.1% (w/w) MeOSSPO, less than about 0.2% (w/w) MeOOSPS, less than
about 0.3% (w/w) malathion carboxylic acid and/or less than about 0.02%
(w/w) isomalathion; (iii) greater than about 99.0% (w/w) malathion, less
than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and/or
less than about 0.1% (w/w) MeOSSPS, 0.03% (w/w) malathion carboxylic
acids and less than about 0.02% (w/w) isomalathion; and, (iv) greater
than about 99.0% (w/w) malathion, less than about 0.04% (w/w) MeOOSPO,
less than about 0.02% (w/w) MeOSSPO and/or less than about 0.1% (w/w)
MeOSSPS, 0.03% (w/w) malathion carboxylic acids and less than about 0.02%
(w/w) isomalathion.

[0073] The malathion prepared by the process of the invention was tested
for storage stability. Malathion prepared by the process of the invention
was stored under a variety of different temperature and humidity
conditions for up to three (3) months. The storage conditions were: (i)
5° C., (ii) 25° C., 60% relative humidity and (iii)
30° C. and 60% relative humidity. The purity of the sample was
determined after storage using HPLC. After storage, the malathion
prepared by the process of the invention exhibits the following with
respect to isomalathion and malathion:

(i) less than about 0.1% (w/w) isomalathion and greater than 98.5% (w/w)
malathion after storage at 5° C. for 3 months; (ii) less than
about 0.1% (w/w) isomalathion and greater than about 98.5% (w/w)
malathion after storage for 3 months at 25° C. and 60% relative
humidity; and, (iii) less than about 0.1% (w/w) isomalathion and greater
than about 98.5% (w/w) malathion after storage for 3 months at 30°
C. and 60% relative humidity.

[0075] The present invention provides an improved process for preparing
pharmaceutical grade malathion. In one embodiment, the present invention
provides a process for preparing malathion, comprising the steps of:
[0076] (a) reacting a phosphorus sulfide with methanol in an organic
solvent to form an organic solution of O,O-dimethyldithiophosphoric acid;
[0077] (b) extracting O,O-dimethyldithiophosphoric acid from the organic
solution into water to form an aqueous solution of
O,O-dimethyldithiophosphoric acid; and [0078] (c) reacting the aqueous
solution of O,O-dimethyldithiophosphoric acid with diethyl maleate to
form malathion.

[0079] For example, we have found that the malathion obtained after step
(c) typically contains less than 0.5% (w/w) of malaoxon, less than 0.1%
(w/w) of isomalathion, less than 0.1% (w/w) of methyl malathion, and less
than 0.3% (w/w) of tetraethyl dithiodisuccinate. In a specific example,
we have found that the malathion obtained after step (c) contained less
than 0.05% (w/w) of malaoxon, less than 0.04% (w/w) of isomalathion, less
than 0.03% (w/w) of methyl malathion, and less than 0.05% (w/w) of
tetraethyl dithiodisuccinate. If these impurities are present in
malathion, they are very difficult to remove.

[0080] Preferably, the malathion obtained after step (c) contains less
than 0.2% (w/w) of malaoxon. More preferably, the malathion obtained
after step (c) contains less than 0.1% (w/w) of malaoxon. More
preferably, the malathion obtained after step (c) contains less than
0.05% (w/w) of malaoxon.

[0081] Preferably, the malathion obtained after step (c) contains less
than 0.07% (w/w) of isomalathion. More preferably, the malathion obtained
after step (c) contains less than 0.04% (w/w) of isomalathion.

[0082] Preferably, the malathion obtained after step (c) contains less
than 0.08% (w/w) of methyl malathion. More preferably, the malathion
obtained after step (c) contains less than 0.03% (w/w) of methyl
malathion.

[0083] Preferably, the malathion obtained after step (c) contains less
than 0.2% (w/w) of tetraethyl dithiodisuccinate. More preferably, the
malathion obtained after step (c) contains less than 0.1% (w/w) of
tetraethyl dithiodisuccinate. More preferably, the malathion obtained
after step (c) contains less than 0.05% (w/w) of tetraethyl
dithiodisuccinate.

Purification of Malathion

[0084] Removing Diethyl Fumarate Impurity

[0085] Crude malathion prepared from diethyl maleate is typically
contaminated with a significant amount of diethyl fumarate (e.g.,
≧2% (w/w)). As previously discussed, it is very difficult to
remove impurities such as diethyl fumarate from malathion using
conventional purification processes (e.g., crystallization or
distillation of malathion).

[0086] In another embodiment, the present invention provides a process for
purifying malathion contaminated with diethyl fumarate, comprising the
steps of: [0087] (a) preparing an acidic aqueous solution containing at
least one sulfur reagent selected from the group consisting of
bisulfites, sulfites, and sulfides; and [0088] (b) contacting the
contaminated malathion with the acidic aqueous solution at a pH below 7
to remove at least about 50% (w/w) of the diethyl fumarate from the
contaminated malathion,

[0089] wherein the purified malathion contains less than 0.2% (w/w) of
tetraethyl dithiodisuccinate.

[0090] Without wishing to be bound by theory, it is believed that the
present purification process operates by converting the diethyl fumarate
impurity into a sulfur derivative, which is water-soluble and is removed
into the aqueous phase. Specifically, it is believed that the sulfur
reagent reacts with the carbon-carbon double bond of diethyl fumarate to
create an ionic, water-soluble derivative containing a carbon-sulfur
bond.

[0091] Surprisingly, we have discovered that if step (b) is performed at
an acidic pH (i.e., below pH 7), the purified malathion contains less
than 0.2% (w/w) of tetraethyl dithiodisuccinate. Preferably, the purified
malathion contains 0.1% (w/w) or less of tetraethyl dithiodisuccinate.
More preferably, the purified malathion contains 0.05% (w/w) or less of
tetraethyl dithiodisuccinate

[0092] We have further discovered that the rate of the step (b) reaction
is slower at lower pH. Preferably, step (b) is performed at a pH of about
3 or above. More preferably, step (b) is performed at a pH of about 5 or
above. More preferably, step (b) is performed at a pH of about 6.

[0093] As previously stated, an aqueous solution of a bisulfite is
inherently acidic, having a pH of about 3-4. Suitable methods for
increasing the pH of an aqueous solution of a bisulfite include, but are
not limited to, adding a base to the aqueous solution. Suitable bases
include, but are not limited to, sodium hydroxide and potassium
hydroxide. Suitable bases further include sulfites and sulfides.

[0094] Step (b) may be performed at any suitable temperature. Preferably,
step (b) is performed at a temperature of about 20° C. to about
65° C. More preferably, step (b) is performed at ambient
temperature.

[0095] At least about 50% (w/w) of the diethyl fumarate is removed from
the contaminated malathion during step (b). Preferably, at least about
70% (w/w) of the diethyl fumarate is removed from the contaminated
malathion during step (b). More preferably, at least about 90% (w/w) of
the diethyl fumarate is removed from the contaminated malathion during
step (b). More preferably, at least about 95% (w/w) of the diethyl
fumarate is removed from the contaminated malathion during step (b). More
preferably, at least about 98% (w/w) of the diethyl fumarate is removed
from the contaminated malathion during step (b). More preferably, at
least about 99% (w/w) of the diethyl fumarate is removed from the
contaminated malathion during step (b).

[0096] Preferably, the purified malathion contains 0 1% (w/w) or less of
diethyl fumarate. More preferably, the purified malathion contains 0.05%
(w/w) or less of diethyl fumarate.

[0097] Removing O,O,S-trimethyl phosphorodithioate (MeOOSPS) Impurity

[0098] Crude malathion prepared from O,O-dimethyldithiophosphoric acid is
typically contaminated with a significant amount of O,O,S-trimethyl
phosphorodithioate (MeOOSPS) (e.g., ≧2% (w/w)). As previously
discussed, it is very difficult to remove impurities such as MeOOSPS from
malathion using conventional purification processes (e.g.,
crystallization or distillation of malathion).

[0099] In another embodiment, the present invention provides a process for
purifying malathion contaminated with O,O,S-trimethyl phosphorodithioate,
comprising the steps of: [0100] (a) mixing the contaminated malathion
with water; and [0101] (b) distilling water from the mixture at a
temperature of about 60° C. or lower, to remove at least about 50%
(w/w) of the O,O,S-trimethyl phosphorodithioate from the contaminated
malathion, [0102] wherein the purified malathion contains 0.1% (w/w) or
less of isomalathion.

[0103] Without wishing to be bound by theory, it is believed that
O,O,S-trimethyl phosphorodithioate forms an azeotrope with water, and
that the present process operates by removing this azeotrope from the
contaminated malathion.

[0104] Any suitable amount of water may be mixed with the contaminated
malathion in step (a). Preferably, the ratio of water to contaminated
malathion in step (a) is at least about 1:1 (w/w). More preferably, the
ratio of water to contaminated malathion in step (a) is at least about
3:1 (w/w).

[0105] The process of the present invention removes at least about 50%
(w/w) of the O,O,S-trimethyl phosphorodithioate from the contaminated
malathion. Preferably, at least about 70% (w/w) of the O,O,S-trimethyl
phosphorodithioate is removed from the contaminated malathion. More
preferably, at least about 90% (w/w) of the O,O,S-trimethyl
phosphorodithioate is removed from the contaminated malathion. More
preferably, at least about 95% (w/w) of the O,O,S-trimethyl
phosphorodithioate is removed from the contaminated malathion. More
preferably, at least about 97% (w/w) of the O,O,S-trimethyl
phosphorodithioate is removed from the contaminated malathion. More
preferably, at least about 99% (w/w) of the O,O,S-trimethyl
phosphorodithioate is removed from the contaminated malathion.

[0106] Preferably, the purified malathion contains 0.2% (w/w) or less of
O,O,S-trimethyl phosphorodithioate. More preferably, the purified
malathion contains 0.1% (w/w) or less of O,O,S-trimethyl
phosphorodithioate.

[0107] Preparation of Pharmaceutical Grade Malathion

[0108] The above-described embodiments of the present invention may be
performed sequentially to produce pharmaceutical grade malathion. In
another embodiment, the present invention provides a process for
preparing pharmaceutical grade malathion, comprising the steps of:

[0109] (a) reacting a phosphorus sulfide with methanol in an organic
solvent to form an organic solution of O,O-dimethyldithiophosphoric acid;

[0110] (b) extracting O,O-dimethyldithiophosphoric acid from the organic
solution into water to form an aqueous solution of
O,O-dimethyldithiophosphoric acid;

[0111] (c) reacting the aqueous solution of O,O-dimethyldithiophosphoric
acid with diethyl maleate to form malathion;

[0112] (d) preparing an acidic aqueous solution containing at least one
sulfur reagent selected from the group consisting of bisulfites,
sulfites, and sulfides;

[0113] (e) contacting the malathion with the acidic aqueous solution at a
pH below 7;

[0114] (f) mixing the malathion with water; and

[0115] (g) distilling water from the mixture at a temperature of about
60° C. or lower, to form pharmaceutical grade malathion.

[0116] Preferably, the process further comprises after step (a) and before
step (b) the steps of:

[0117] (i) filtering the organic solution of O,O-dimethyldithiophosphoric
acid; and

[0119] Preferably, the pharmaceutical grade malathion contains 0.2% (w/w)
or less of tetraethyl dithiodisuccinate. More preferably, the
pharmaceutical grade malathion contains 0.1% (w/w) or less of tetraethyl
dithiodisuccinate. More preferably, the pharmaceutical grade malathion
contains 0.05% (w/w) or less of tetraethyl dithiodisuccinate.

[0120] Preferably, the pharmaceutical grade malathion contains 0.1% (w/w)
or less of O,O,S-trimethyl phosphorothioate (MeOOSPO). More preferably,
the pharmaceutical grade malathion contains 0.05% (w/w) or less of
O,O,S-trimethyl phosphorothioate (MeOOSPO). More preferably, the
pharmaceutical grade malathion contains 0.04% (w/w) or less of
O,O,S-trimethyl phosphorothioate (MeOOSPO).

[0121] Preferably, the pharmaceutical grade malathion contains 0.1% (w/w)
or less of O,S,S-trimethyl phosphorodithioate (MeOSSPO). More preferably,
the pharmaceutical grade malathion contains 0.05% (w/w) or less of
O,S,S-trimethyl phosphorodithioate (MeOSSPO). More preferably, the
pharmaceutical grade malathion contains 0.02% (w/w) or less of
O,S,S-trimethyl phosphorodithioate (MeOSSPO).

[0122] Preferably, the pharmaceutical grade malathion contains 0.1% (w/w)
or less of malaoxon. More preferably, the pharmaceutical grade malathion
contains 0.05% (w/w) or less of malaoxon.

[0123] Preferably, the pharmaceutical grade malathion contains 0.2% (w/w)
or less of O,O,S-trimethyl phosphorodithioate (MeOOSPS). More preferably,
the pharmaceutical grade malathion contains 0.1% (w/w) or less of
O,O,S-trimethyl phosphorodithioate (MeOOSPS). More preferably, the
pharmaceutical grade malathion contains 0.05% (w/w) or less of
O,O,S-trimethyl phosphorodithioate (MeOOSPS).

[0124] Preferably, the pharmaceutical grade malathion contains 0.2% (w/w)
or less of diethyl fumarate. More preferably, the pharmaceutical grade
malathion contains 0.1% (w/w) or less of diethyl fumarate. More
preferably, the pharmaceutical grade malathion contains 0.05% (w/w) or
less of diethyl fumarate. More preferably, the pharmaceutical grade
malathion contains 0.01% (w/w) or less of diethyl fumarate.

[0125] Preferably, the pharmaceutical grade malathion contains 0.2% (w/w)
or less of dimethyl malathion. More preferably, the pharmaceutical grade
malathion contains 0.1% (w/w) or less of dimethyl malathion. More
preferably, the pharmaceutical grade malathion contains 0.05% (w/w) or
less of dimethyl malathion. More preferably, the pharmaceutical grade
malathion contains 0.02% (w/w) or less of dimethyl malathion.

[0126] Preferably, the pharmaceutical grade malathion contains 0.2% (w/w)
or less of methyl malathion. More preferably, the pharmaceutical grade
malathion contains 0.1% (w/w) or less of methyl malathion. More
preferably, the pharmaceutical grade malathion contains 0.06% (w/w) or
less of methyl malathion.

[0128] Preferably, the pharmaceutical grade malathion contains 0.1% (w/w)
or less of isomalathion. More preferably, the pharmaceutical grade
malathion contains 0.05% (w/w) or less of isomalathion. More preferably,
the pharmaceutical grade malathion contains 0.02% (w/w) or less of
isomalathion.

[0130] Preferably, the process of the present invention is performed at a
commercial scale. Preferably, the pharmaceutical grade malathion is
produced as a single batch of at least about 100 grams. More preferably,
the pharmaceutical grade malathion is produced as a single batch of at
least about 500 grams. More preferably, the pharmaceutical grade
malathion is produced as a single batch of at least about one (1)
kilogram.

Pharmaceutical Grade Malathion

[0131] In another embodiment, the present invention provides a composition
of pharmaceutical grade malathion, which contains 0.1% (w/w) or less of
isomalathion, and 0.1% (w/w) or less of each individual unknown impurity
present in the composition.

[0132] Preferably, the composition contains 0.05% (w/w) or less of
isomalathion. More preferably, the composition contains 0.02% (w/w) or
less of isomalathion.

[0133] Preferably, the composition contains less than 0.5% (w/w) of
O,O,S-trimethyl phosphorothioate (MeOOSPO). More preferably, the
composition contains less than 0.04% (w/w) of O,O,S-trimethyl
phosphorothioate (MeOOSPO).

[0134] Preferably, the composition contains less than 0.1% (w/w) of methyl
malathion. More preferably, the composition contains 0.08% (w/w) or less
of methyl malathion. More preferably, the composition contains 0.06%
(w/w) or less of methyl malathion.

[0135] Preferably, the composition contains less than 0.05% (w/w) of
O,O,S-trimethyl phosphorothioate (MeOOSPO) and less than 0.1% (w/w) of
methyl malathion. More preferably, the composition contains 0.05% (w/w)
or less of isomalathion, less than 0.04% (w/w) of O,O,S-trimethyl
phosphorothioate (MeOOSPO), and 0.08% (w/w) or less of methyl malathion.
More preferably, the composition contains 0.02% (w/w) or less of
isomalathion, less than 0.04% (w/w) of O,O,S-trimethyl phosphorothioate
(MeOOSPO), and 0.06% (w/w) or less of methyl malathion.

[0136] Preferably, the composition is produced as a single batch of at
least about 100 grams. More preferably, the composition is produced as a
single batch of at least about 500 grams. More preferably, the
composition is produced as a single batch of at least about one (1)
kilogram.

[0137] Preferably, the composition is a commercial scale composition.

[0138] In another embodiment, the present invention provides a
pharmaceutical formulation comprising the composition of pharmaceutical
grade malathion.

[0139] In another embodiment, the present invention provides a process for
preparing a pharmaceutical formulation of the composition of
pharmaceutical grade malathion, comprising the step of mixing the
composition of pharmaceutical grade malathion with at least one
pharmaceutically acceptable excipient.

Storage Stable Commercial Scale Composition of Malathion

[0140] Surprisingly, the pharmaceutical grade malathion prepared in
accordance with the present invention maintains a low level of
isomalathion and other impurities during storage. In another embodiment,
the present invention provides a commercial scale composition of
pharmaceutical grade malathion, which contains 0.1% (w/w) or less of
isomalathion after storing the composition for three (3) months at
25° C.±2° C. and 60%±5% relative humidity.

[0141] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.05% (w/w) or less of isomalathion after
storing the composition for three (3) months at 25°
C.±2° C. and 60%±5% relative humidity. More preferably, the
commercial scale composition of pharmaceutical grade malathion contains
0.04% (w/w) or less of isomalathion after storing the composition for
three (3) months at 25° C.±2° C. and 60%±5% relative
humidity.

[0142] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of isomalathion after storing
the composition for three (3) months at 30° C.±2° C. and
60%±5% relative humidity. More preferably, the commercial scale
composition of pharmaceutical grade malathion contains 0.06% (w/w) or
less of isomalathion after storing the composition for three (3) months
at 30° C.±2° C. and 60%±5% relative humidity.

[0143] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of isomalathion after storing
the composition for two (2) months at 40° C.±2° C. and
75%±5% relative humidity. More preferably, the commercial scale
composition of pharmaceutical grade malathion contains 0.1% (w/w) or less
of isomalathion after storing the composition for three (3) months at
40° C.±2° C. and 75%±5% relative humidity.

[0144] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains less than 0.1% (w/w) of methyl malathion after
storing the composition for three (3) months at 30°
C.±2° C. and 60%±5% relative humidity. More preferably, the
commercial scale composition of pharmaceutical grade malathion contains
0.06% (w/w) or less of methyl malathion after storing the composition for
three (3) months at 30° C.±2° C. and 60%±5% relative
humidity.

[0145] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains less than 0.1% (w/w) of methyl malathion after
storing the composition for three (3) months at 40°
C.±2° C. and 75%±5% relative humidity. More preferably, the
commercial scale composition of pharmaceutical grade malathion contains
0.06% (w/w) or less of methyl malathion after storing the composition for
three (3) months at 40° C.±2° C. and 75%±5% relative
humidity.

[0146] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains less than 0.05% (w/w) of O,O,S-trimethyl
phosphorothioate (MeOOSPO) after storing the composition for three (3)
months at 30° C.±2° C. and 60%±5% relative humidity.
More preferably, the commercial scale composition of pharmaceutical grade
malathion contains 0.04% (w/w) or less of O,O,S-trimethyl
phosphorothioate (MeOOSPO) after storing the composition for three (3)
months at 30° C.±2° C. and 60%±5% relative humidity.

[0147] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains less than 0.05% (w/w) of O,O,S-trimethyl
phosphorothioate (MeOOSPO) after storing the composition for two (2)
months at 40° C.±2° C. and 75%±5% relative humidity.
More preferably, the commercial scale composition of pharmaceutical grade
malathion contains 0.05% (w/w) or less of methyl malathion after storing
the composition for three (3) months at 40° C.±2° C. and
75%±5% relative humidity.

[0148] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each individual unknown
impurity present in the composition after storing the composition for
three (3) months at 25° C.±2° C. and 60%±5% relative
humidity. More preferably, the commercial scale composition of
pharmaceutical grade malathion contains 0.06% (w/w) or less of each
individual unknown impurity present in the composition after storing the
composition for three (3) months at 25° C.±2° C. and
60%±5% relative humidity.

[0149] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each individual unknown
impurity present in the composition after storing the composition for
three (3) months at 5° C.±3° C. and ambient relative
humidity. More preferably, the commercial scale composition of
pharmaceutical grade malathion contains 0.06% (w/w) or less of each
individual unknown impurity present in the composition after storing the
composition for three (3) months at 5° C.±2° C. and
ambient relative humidity. More preferably, the commercial scale
composition of pharmaceutical grade malathion contains 0.04% (w/w) or
less of each individual unknown impurity present in the composition after
storing the composition for three (3) months at 5° C.±2°
C. and ambient relative humidity.

[0150] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each individual unknown
impurity present in the composition after storing the composition for two
(2) months at 30° C.±2° C. and 60%±5% relative
humidity.

[0151] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.15% (w/w) or less of each individual unknown
impurity present in the composition after storing the composition for
three (3) months at 30° C.±2° C. and 60%±5% relative
humidity.

[0152] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each individual unknown
impurity present in the composition after storing the composition for one
(1) month at 40° C.±2° C. and 75%±5% relative
humidity.

[0153] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each impurity present in
the composition after storing the composition for three (3) months at
25° C.±2° C. and 60%±5% relative humidity. More
preferably, the commercial scale composition of pharmaceutical grade
malathion contains 0.06% (w/w) or less of each impurity present in the
composition after storing the composition for three (3) months at
25° C.±2° C. and 60%±5% relative humidity.

[0154] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each impurity present in
the composition after storing the composition for three (3) months at
5° C.±3° C. and ambient relative humidity. More
preferably, the commercial scale composition of pharmaceutical grade
malathion contains 0.06% (w/w) or less of each impurity present in the
composition after storing the composition for three (3) months at
5° C.±2° C. and ambient relative humidity. More
preferably, the commercial scale composition of pharmaceutical grade
malathion contains 0.04% (w/w) or less of each impurity present in the
composition after storing the composition for three (3) months at
5° C.±2° C. and ambient relative humidity.

[0155] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each impurity present in
the composition after storing the composition for two (2) months at
30° C.±2° C. and 60%±5% relative humidity.
Preferably, the commercial scale composition of pharmaceutical grade
malathion contains 0.15% (w/w) or less of each impurity present in the
composition after storing the composition for three (3) months at
30° C.±2° C. and 60%±5% relative humidity.

[0156] Preferably, the commercial scale composition of pharmaceutical
grade malathion contains 0.1% (w/w) or less of each impurity present in
the composition after storing the composition for one (1) month at
40° C.±2° C. and 75%±5% relative humidity.

Methodology and Protocols

In-Process Purity Determination by HPLC

[0157] Purity was determined using a high performance liquid
chromatography (HPLC) instrument with a variable wavelength detector.

[0161] Each known impurity (about ten (10) mg) was added to a 10-mL
volumetric flask, and the flask was then filled to volume with diluent. A
2.5 mL aliquot of this solution was transferred to 25-mL volumetric
flask, and the flask was then filled to volume with diluent to provide
the Known Impurities Stock Solution.

[0162] A malathion working standard (about fifty (50) mg) and diluent
(about fifteen (15) mL) were added to a 25-mL volumetric flask, and the
solution mixed to dissolve. To the flask was added five (5) mL of, the
Known Impurities Stock Solution, and the flask was then filled to volume
with diluent to provide the Known Impurities Resolution Solution.

[0163] (c) Malathion Sample Solution

[0164] Approximately one hundred (100) mg of the malathion sample to be
assayed, accurately weighed, was transferred into a 50-mL volumetric
flask, and the flask was then filled to volume with diluent to provide
the Malathion Sample Solution.

[0165] (d) System Suitability Test

[0166] The Known Impurities Resolution Solution was injected into the HPLC
system. The resolution factor between isomalathion and MeOOSPS was not
less than 1.7. The resolution factor between MeOOSPS and diethyl fumarate
was not less than 1.7. The resolution factor between diethyl fumarate and
dimethyl malathion was not less than 2.0. Resolution factors were
calculated according to the United States Pharmacopeia (USP) <621>.
Typical chromatographic parameters are listed in the following table:

[0182] Approximately one hundred (100) mg of malathion working standard,
accurately weighed, was transferred into a 50-mL volumetric flask, and
the flask was then filled to volume with diluent to provide the Malathion
Standard Solution.

[0183] (d) Known Impurities Standard Solution

[0184] An aliquot (2.5 mL) of the Malathion Standard Solution was
transferred into a 50-mL volumetric flask, and the flask was then filled
to volume with diluent. An aliquot (2.5 mL) of the obtained solution was
transferred into a 25-mL volumetric flask, and the flask was then filled
to volume with diluent to provide the Known Impurities Standard Solution.

[0185] (e) Malathion Sample Solution

[0186] See above (In-Process Purity Determination by HPLC).

[0187] (f) System Suitability Test

[0188] One (1) injection of the Known Impurities Resolution Solution, six
(6) replicate injections of the Known Impurities Standard Solution, and
five (5) replicate injections of the Malathion Standard Solution were
made.

[0189] The resolution factor between MeOSSPO and MeOOSPO was not less than
1.7. The resolution factor between MeOOSPS and diethyl fumarate was not
less than 1.7. The resolution factor between diethyl fumarate and
dimethyl malathion was not less than 2.0. Resolution factors were
calculated according to the United States Pharmacopeia (USP) <621>.

[0190] The relative standard deviation of five (5) replicate injections of
the Malathion Standard Solution was not more than 2.0%. The relative
standard deviation of six (6) replicate injections of the Known
Impurities Standard Solution was not more than 10.0%. If necessary, the
mobile phase composition and/or flow rate were adjusted to meet the
chromatographic parameters. Typical chromatographic parameters are listed
in the table in Example 9.

End-of-Process Determination of Isomalathion

[0191] Isomalathion content was determined using a high performance liquid
chromatography (HPLC) instrument with a variable wavelength detector.

[0194] Isomalathion (about ten (10) mg) was added to a 20-mL volumetric
flask, and the flask was then filled to volume with diluent to provide
the Isomalathion Stock Solution.

[0195] A malathion working standard (about one hundred (100) mg),
accurately weighed was added to a 50-mL volumetric flask. To the flask
was added 2.0 mL of the Isomalathion Stock Solution, and the flask was
then filled to volume with diluent to provide the Isomalathion Resolution
Solution.

[0196] (c) Isomalathion Standard Solution

[0197] The Isomalathion Standard Solution was prepared in the same way as
the Known Impurities Standard Solution (see above).

[0198] (d) Malathion Sample Solution

[0199] See above (In-Process Purity Determination by HPLC).

[0200] (e) System Suitability Test

[0201] One (1) injection of the Isomalathion Resolution Solution and six
(6) replicate injections of the Isomalathion Standard Solution were made.

[0202] The relative standard deviation of six (6) replicate injections of
the Isomalathion Standard Solution was not more than 10.0%. If necessary,
the mobile phase composition and/or flow rate were adjusted to meet the
chromatographic parameters. Typical chromatographic parameters are listed
in the table in Example 9.

[0210] The malathion prepared by the process of the invention may be used
for the preparation of malathion formulations such as Ovide® lotion
and gels (see, U.S. Patent Application No. PCT/US05/24643 and 24558),
lotions, creams or solutions.

The invention is further illustrated, but not limited by, the following
examples.

Example 1

Preparation of Dimethyl Dithiophosphoric Acid

[0211] Phosphorus pentasulfide (1.4 kg) and toluene (1.4 L) were combined
under nitrogen in a 5-L jacketed glass reactor equipped with mechanical
stirrer, and the resulting suspension was heated with stirring to about
60° C. Methanol (1.1 L) was added dropwise over the course of four
(4) hours and fifteen (15) minutes, while maintaining the temperature of
the reaction mass at 67° C. or lower. The resulting gaseous
H2S was trapped using an aqueous solution of sodium
hypochlorite/sodium hydroxide. After complete addition of the methanol,
the mixture was stirred at 55-65° C. for an additional one (1)
hour.

[0212] The mixture was cooled to a temperature of 22-30° C. and the
mixture was filtered to remove unreacted phosphorus pentasulfide.
Additional toluene (0.3 L) was added to the resulting filtrate. The
mixture was distilled under vacuum (≦200 mbar) at a temperature of
about 50-60° C. to remove about 600 mL of toluene. The resulting
concentrate was cooled to a temperature of 22-30° C. and water (3
kg) was added. The two phases were mixed for 20 minutes, and then the
phases were separated. The aqueous phase was washed with toluene (0.3 L),
and the aqueous phase again was separated, to provide an aqueous solution
of dimethyldithiophosphoric acid (about 4.22 kg containing about 1.22 kg
of dimethyldithiophosphoric acid).

Example 2

Preparation of Malathion

[0213] The solution of dimethyl dithiophosphoric acid was added to diethyl
maleate (the ratio of dimethyl dithiophosphoric acid to diethyl maleate
was approximately 1-1.25 kg:1.2 kg). Hydroquinone (approximately 3 grams)
was added to the mixture. The reaction mixture which contains two
separate solutions, an organic solution of diethyl maleate and an aqueous
solution of dimethyl dithiophosphoric acid, was mixed for about 8 hours
at 53° C. under a nitrogen atmosphere. After mixing, the reaction
was cooled to ambient temperature and the organic and aqueous solutions
were separated. The organic or diethyl maleate solutions which contained
malathion was washed two (2) times with water (approximately 1 liter each
time). The organic and aqueous solutions were separated and the malathion
in the solution of diethyl maleate retained. This reaction yielded
approximately 1.5-1.9 kg of malathion.

Example 3

Purification of the Malathion

[0214] The solution of diethylmaleate (organic) which contained the
malathion (approximately 1.5-1.9 kg) was treated with about 4.6 kg of a
20% sodium bisulfite solution (aqueous) (pH 6.1-6.3) at 60° C. for
2 hours. The mixture was cooled to ambient temperature and the organic
and aqueous layers separated; the organic layer was washed with water
(approximately 1.5 kg). The organic and aqueous layers were separated.
The organic layer was then washed with a 0.5% NaOH solution. After
separation of the two layers, the organic layer containing the malathion
was washed twice with water (approximately 1 liter of water was used for
each wash) to yield, approximately 0.75-0.95 kg of malathion. The purity
of the malathion at this stage was determined by HPLC. If more than 5%
(w/w) diethyl fumarate was present in the malathion, the material was
reprocessed by treatment with the sodium bisulfite solution and water.
After reprocessing, the malathion was assayed a second time for purity.
This reprocessing step could be repeated until the purity profile of the
malathion conformed with the diethyl fumarate cut-off set forth above.

Example 4

Analysis of Malathion after Purification

[0215] The purity of malathion and the percentage of impurities present
were determined by HPLC instrument with a variable wavelength detector.
The mobile phase composition and/or flow rate were adjusted to meet the
chromatographic parameters. The results of the HPLC analyses for two
different sample batches of malathion are shown below in Table I.

[0216] Water (2.8 kg) was added to the malathion formed as described in
Example 4 and the resulting two-phase mixture subjected to azeotropic
distillation over the course of four days at a temperature of about
35-50° C. and a pressure of about 30-60 mbar. Water was added to
the mixture at approximately one-hour intervals to replace the quantity
removed by azeotropic distillation during that period (about 0.2-0.7 L
each time). A total of about 34.2 L of water was distilled during this
process. The two-phase mixture was cooled to 22-30° C., and the
phases were separated, providing malathion (0.84 kg) (note, the malathion
is wet, i.e., contains water).

[0217] The purity of the obtained malathion was determined using HPLC; the
results are shown in Table II.

[0218] These data demonstrate that at least 97% (w/w) of the MeOOSPS was
removed from the malathion of Example 3. These data further demonstrate
that the purified malathion contained only 0.07% (w/w) of isomalathion.

Example 6

Analysis of Sample Batches of Malathion Prepared by the Process of this
Invention

[0219] In Table III set forth below, three different batches of malathion
prepared by the process of the invention (these batches are noted in the
table as A, B and C) were analyzed after drying by HPLC for malathion
purity and for the presence of impurities as set forth above. As a
comparison, the following samples of malathion were analyzed, malathion
approved for pharmaceutical use from the United States Pharmacopeia
("USP") and malathion used for pharmaceutical preparations obtained from
Cheminova (referred to herein as, Cheminova A/S, Thyboronvej 78 DK-7673
Harboore, Denmark). The purity of these samples, USP and Cheminova, was
compared with the purity of the malathion prepared by the process of the
invention. The results of the analysis are shown in Table III.

[0221] When compared with malathion from Cheminova, malathion prepared by
the methods of the present invention has less isomalathion, <0.02%
(w/w) versus 0.2% (w/w) malathion from Cheminova. In addition, there is
less (i) MeOOSPO present, <0.02% (w/w), malathion prepared by the
methods of the present invention, versus 0.05% (w/w), USP malathion, (ii)
diethyl fumarate, <0.01% (w/w), malathion prepared by the methods of
the present invention, versus 0.02% (w/w), malathion from Cheminova, and,
(iii) methyl malathion, 0.06-0.07% (w/w), malathion prepared by the
methods of the present invention versus 0.1-0.2% (w/w), malathion from
Cheminova.

[0222] In one embodiment, the malathion prepared by the process of the
present invention, comprises, malathion greater than about 98.0% (w/w)
malathion and less than about 0.1% (w/w) isomalathion and less than 0.1%
(w/w) malathion monoacid. In another embodiment, the malathion prepared
by the process of the present invention contains greater than about 98.0%
(w/w) malathion and less than about 0.05% (w/w) isomalathion. In a third
embodiment, the amount of isomalathion present is less than about 0.02%
(w/w).

[0223] The malathion prepared by the process of the invention may also
contain greater than about 98.5% (w/w) malathion, less than about 0.2%
(w/w) MeOOSPS, less than about 0.1% (w/w) malaoxon, less than about 0.2%
(w/w) diethyl fumarate, less than abut 0.2% (w/w) dimethylmalathion, less
than about 0.3% (w/w) methylmalathion, and less than about 0.1% (w/w)
isomalathion. In another embodiment, the malathion prepared by the
process of the invention contains greater than about 99.0% (w/w)
malathion, less than about 0.1% (w/w) MeOOSPS, less than about 0.05%
(w/w) malaoxon, less than about 0.01% (w/w) diethyl fumarate, less than
about 0.02% (w/w) dimethylmalathion, less than about 0.07% (w/w)
methylmalathion, and less than about 0.02% (w/w) isomalathion. In each of
the embodiments listed above for malathion prepared by the process of the
invention, the amount of any other detectable impurity may be less than
0.1% (w/w).

[0224] Embodiments of malathion at this stage of the purification include:

(i) greater than about 98.5% (w/w) malathion, less than about 0.1% (w/w)
MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.1% (w/w)
malaxon, less than about 0.2% (w/w) MeOOSPS, less than about 0.2% (w/w)
diethyl fumarate, less than about 0.3% (w/w) methyl malathion, and/or
less than about 0.1% (w/w) isomalathion; (ii) greater than about 98.5%
(w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1%
(w/w) MeOSSPO, less than about 0.1% (w/w) malaxon, less than about 0.2%
(w/w) MeOOSPS, less than about 0.2% (w/w) diethyl fumarate, less than
about 0.3% (w/w) methyl malathion, less than about 0.3% (w/w) O,O methyl,
ethyl S-(1,2-dicarboethoxy)ethyl phosphorodithioate, less than about 0.3%
(w/w) malathion carboxylic acids and/or less than about 0.1% (w/w)
isomalathion; (iii) greater than about 99.0% (w/w) malathion, less than
about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than
about 0.1% (w/w) malaxon, less than about 0.2% (w/w) MeOOSPS, less than
about 0.2% (w/w) diethyl fumarate, less than about 0.3% (w/w) methyl
malathion, and/or less than about 0.1% (w/w) isomalathion; (iv) greater
than about 99.0% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO,
less than about 0.1% (w/w) MeOSSPO, less than about 0.1% (w/w) malaxon,
less than about 0.2% (w/w) MeOOSPS, less than about 0.2% (w/w) diethyl
fumarate, less than about 0.3% (w/w) methyl malathion, less than about
0.3% (w/w) O,O methyl, ethyl S-(1,2-dicarboethoxy)ethyl
phosphorodithioate, less than about 0.3% (w/w) malathion, less than about
0.3% (w/w) malathion carboxylic acids
(O,O-dimethyl-S-(1-carboxy-2-carboxyethoxy) ethyl phosphorodithioate
and/or O,O-dimethyl-S-(1-carboxy-2-carboxy) ethyl phosphorodithioate)
less than 0.1% (w/w) isomalathion; (v) greater than about 99.0% (w/w)
malathion, less than about 0.1% (w/w) isomalathion and/or less than about
0.3% (w/w) malathion carboxylic acids; (vi) greater than about 99.0%
(w/w) malathion, less than about 0.02% (w/w) isomalathion and/or less
than about 0.03% (w/w) malathion carboxylic acids; (vii) greater than
about 99.0% (w/w) malathion, less than about 0.02% (w/w) isomalathion,
less than about 0.03% (w/w) malathion carboxylic acids, less than about
0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and/or less than
about 0.2% (w/w) MeOSSPS; and, (viii) greater than about 99.0% (w/w)
malathion, less than about 0.02% (w/w) isomalathion, less than about
0.03% (w/w) malathion carboxylic acids, less than about 0.04% (w/w)
MeOOSPO, less than about 0.02% (w/w) MeOSSPO and/or less than about 0.1%
(w/w) MeOSSPS. Additionally, in any of the above embodiments, there may
be less than 0.1% (w/w) of any other detectable impurity present in the
malathion at this stage of the purification.

Example 7

Storage Stability of Malathion

[0225] Table IV presents the analytical data showing storage of two,
different batches of malathion after storage under a variety of different
conditions.

[0226] Table IV shows the results of the HPLC analysis after three months
of storage conditions under these test conditions for two different
batches of malathion prepared by the process of this invention.

[0227] The invention provides for a malathion characterized by the fact
that it is stable after storage under a variety of different conditions.
Stability may be characterized by the fact that the levels of
isomalathion, MeOOSPO, MeOSSPO and MeOOSPS do not exceed 0.2% (w/w) after
storage.

[0228] After storage at 5° C. for 3 months, the malathion may have
the following purity/impurity profile, greater than about 98.5% (w/w)
malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w)
MeOSSPO, less than about 011% (w/w) malaxon, less than about 0.2% (w/w)
MeOOSPS, less than about 0.2% (w/w) diethyl fumarate, less than about
0.2% (w/w) dimethylmalathion, less than about 0.3% (w/w) methylmalathion
and/or less than about 0.1% (w/w) isomalathion. In another embodiment,
the profile for the malathion after storage at 5° C. for 3 months
is greater than about 99.7% (w/w) malathion, less than about 0.04% (w/w)
MeOOSPO, less than about 0.02% (w/w) MeOSSPO, less than about 0.05% (w/w)
malaxon, less than about 0.1% (w/w) MeOOSPS, less than about 0.01% (w/w)
diethyl fumarate, less than about 0.02% (w/w) dimethylmalathion, less
than about 0.06% (w/w) methylmalathion and/or less than about 0.05% (w/w)
isomalathion.

[0229] After storage for 3 months at 25° C., 60% relative humidity
the malathion may have the following purity/impurity profile, greater
than about 98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO,
less than about 0.1% (w/w) MeOSSPO, less than about 0.1% (w/w) malaxon,
less than about 0.2% (w/w) MeOOSPS, less than about 0.2% (w/w) diethyl
fumarate, less than about 0.2% (w/w) dimethylmalathion, less than about
0.3% (w/w) methylmalathion and/or less than about 0.1% (w/w)
isomalathion. In a second embodiment, the malathion has the following
profile after storage for 3 months at 25° C., 60% relative
humidity, greater than about 99.0% (w/w) malathion, less than about 0.04%
(w/w) MeOOSPO, less than about 0.02% (w/w) MeOSSPO, less than about 0.05%
(w/w) malaxon, less than about 0.1% (w/w) MeOOSPS, less than about 0.01%
(w/w) diethyl fumarate, less than about 0.02% (w/w) dimethylmalathion,
less than about 0.06% (w/w) methylmalathion and/or less than about 0.04%
(w/w) isomalathion.

[0230] After storage for 3 months at 30° C. and 60% relative
humidity, the malathion may have the following purity/impurity profile,
greater than about 98.5% (w/w) malathion, less than about 0.1% (w/w)
MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.1% (w/w)
malaxon, less than about 0.2% (w/w) MeOOSPS, less than about 0.2% (w/w)
diethyl fumarate, less than about 0.2% (w/w) dimethylmalathion, less than
about 0.3% (w/w) methylmalathion and/or less than about 0.1% (w/w)
isomalathion. In a second embodiment, the malathion has the following
profile after storage at 30° C., 60% relative humidity, greater
than about 99.0% (w/w) malathion, less than about 0.04% (w/w) MeOOSPO,
less than about 0.02% (w/w) MeOSSPO, less than about 0.05% (w/w) malaxon,
less than about 0.1% (w/w) MeOOSPS, less than about 0.01% (w/w) diethyl
fumarate, less than about 0.02% (w/w) dimethylmalathion, less than about
0.06% (w/w) methylmalathion and/or less than about 0.04% (w/w)
isomalathion.

[0231] After storage for 3 months at 40° C. and 75% relative
humidity, the malathion has the following purity/impurity profile,
greater than about 97.0% (w/w) malathion, less than about 0.1% (w/w)
MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.1% (w/w)
malaxon, less than about 0.2% (w/w) MeOOSPS, less than about 0.2% (w/w)
diethyl fumarate, less than about 0.2% (w/w) dimethylmalathion, less than
about 0.3% (w/w) methylmalathion and/or less than about 0.1% (w/w)
isomalathion. In a second embodiment, the malathion has the following
purity/impurity profile after storage for 3 months at 40° C., 75%
relative humidity, greater than about 97.5% (w/w) malathion, less than
about 0.05% (w/w) MeOOSPO, less than about 0.02% (w/w) MeOSSPO, less than
about 0.05% (w/w) malaxon, less than about 0.2% (w/w) MeOOSPS, less than
about 0.02% (w/w) diethyl fumarate, less than about 0.02% (w/w)
dimethylmalathion, less than about 0.06% (w/w) methylmalathion and/or
less than about 0.1% (w/w) isomalathion.

Example 8

[0232] An example of a lotion formulation prepared using malathion
prepared by the process of the present invention comprises the following
components:

The stability of the malathion prepared by the process of the invention
in a malathion lotion formulation (Table V) was tested under a variety of
different storage conditions. The percentages of impurities under each
storage condition were assayed. The results are shown in Table VI. In one
embodiment, the malathion in the lotion has the following purity/impurity
profile after storage at 5° C. for 3 months, less than about 0.5%
(w/w) diethyl fumarate, less than about 0.5% (w/w) methylmalathion, less
than about 0.1% (w/w) isomalathion, less than about 0.1% (w/w) malaoxon,
and/or less than about 0.5% (w/w) dimethylmalathion. In addition, in this
embodiment, there is less than 0.5% (w/w) of any other detectable
impurity present. In another embodiment, the malathion in the lotion has
the following purity/impurity profile after storage at 5° C. for 3
months, less than about 0.02% (w/w) diethyl fumarate, less than about
0.2% (w/w) methylmalathion, less than about 0.05% (w/w) isomalathion,
less than about 0.03% (w/w) malaxon, and/or less than about 0.03% (w/w)
dimethylmalathion.

[0233] After storage for 3 months at 25° C., 60% relative humidity,
the malathion in the lotion has the following purity/impurity profile,
less than about 0.5% (w/w) diethyl fumarate, less than about 0.5% (w/w)
methylmalathion, less than about 0.1% (w/w) isomalathion, less than about
0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w)
dimethylmalathion. In addition, in this embodiment, there is less than
0.5% (w/w) of any other detectable impurity present. In another
embodiment, the malathion in the lotion has the following purity/impurity
profile after storage at 5° C. for 3 months, less than about 0.01%
(w/w) diethyl fumarate, less than about 0.1% (w/w) methylmalathion, less
than about 0.05% (w/w) isomalathion, less than about 0.03% (w/w) malaxon,
and/or less than about 0.03% (w/w) dimethylmalathion.

[0234] After storage for 3 months at 30° C. and 60% relative
humidity, the malathion in the lotion has the following purity/impurity
profile, less than about 0.5% (w/w) diethyl fumarate, less than about
0.5% (w/w) methylmalathion, less than about 0.1% (w/w) isomalathion, less
than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w)
dimethylmalathion. In this embodiment, there is less than 0.5% (w/w) of
any other detectable impurity present. In a second embodiment under these
storage conditions (30° C. and 60% relative humidity) the
malathion in the lotion has the following purity/impurity profile, less
than about 0.02% (w/w) diethyl fumarate, less than about 0.02% (w/w)
methylmalathion, less than about 0.05% (w/w) isomalathion, less than
about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w)
dimethylmalathion.

[0235] After storage for 3 months at 40° C. and 75% relative
humidity, the malathion in the lotion has the following purity/impurity
profile, less than about 0.5% (w/w) diethyl fumarate, less than about
0.5% (w/w) methylmalathion, less than about 0.1% (w/w) isomalathion, less
than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w)
dimethylmalathion. In this embodiment, there is less than 0.5% (w/w) of
any other detectable impurity present. Under these storage conditions, in
a second embodiment, the malathion in the lotion has the following
profile, less than about 0.01% (w/w) diethyl fumarate, less than about
0.04% (w/w) methylmalathion, less than about 0.07% (w/w) isomalathion,
less than about 0.03% (w/w) malaoxon, and/or less than about 0.22% (w/w)
dimethylmalathion.

[0237] The limit of detection is the minimum concentration (% w/w) at
which the analyte can reliably be detected. The limit of quantitation is
the minimum concentration (% w/w) at which the analyte can reliably be
quantified. Limits of detection and quantitation were determined by
comparing measured signals from samples with known low concentrations of
analyte to measured signals from blank samples. The relative response
factor is the ratio of slopes provided by calibration curves for analyte
and corresponding internal standard (or surrogate and corresponding
internal standard). The resolution is the separation of two peaks in
terms of their average peak width at base (tR2>tR1):

[0254] A solution of dimethyl dithiophosphoric acid in toluene was reacted
with methyl iodide in the presence of sodium carbonate at ambient
temperature and the toluene removed by filtration. The liquid residue was
distilled at 130° C. to produce a colorless liquid.

(b) O,S,S-Trimethyl Phosphorodithioate (MeOSSPO)

##STR00004##

[0256] A solution of dimethyl dithiophosphoric acid in a mixture of
toluene/acetonitrile was refluxed for 20 hours in the presence of KOH.
The potassium salt of S,S-dimethyl phosphorodithioate was precipitated in
an ice/water bath. The salt was collected by filtration. After
filtration, the salt was suspended in acetonitrile and treated with
dimethyl sulfate at the reflux temperature for 6 hours. Water was then
added and the mixture refluxed for 1 hour to destroy excess of the
methylating agent. The reaction mixture was filtered and the solvent
evaporated. The residual residue was extracted into chloroform and the
chloroform layer washed with water. The chloroform layer was dried over
sodium sulfate and the residue vacuum distilled to yield MeOSSPO.

(c) Trimethyl Phosphorothioate (MeOOSPO)

##STR00005##

[0258] A pre-cooled solution of dimethyl dithiophosphoric acid in toluene
was treated with Cl2 while maintaining the reaction temperature
between 5-10° C. The mixture was then heated to the reflux
temperature for 1.5 hours. After cooling to room temperature, an aqueous
solution of KOH was drop wise added to the reaction mixture until a basic
(pH>7.0) was achieved. The organic and aqueous layers were separated
and the aqueous layer evaporated to dryness. Acetonitrile was added to
the solid residue, the mixture filtered and the acetonitrile evaporated.
The residual residue was resuspended in acetonitrile and then treated
with methyl iodide at ambient temperature for 10 hours. The solvent was
evaporated and the residue extracted with ethyl acetate. After
extraction, the ethyl acetate was evaporated to dryness. The residual
liquid was vacuum distilled to yield MeOOSPO.

(d) Isomalathion

##STR00006##

[0260] This product is commercially available from the United States
Pharmacopeia, Reference Standard (B. No. F1B107) (www.usp.org).

[0264] A mixture of malathion, methanol and a catalytic amount of
concentrated sulfuric acid was refluxed for 7 hours. After cooling to
ambient temperature, the solution was treated with aqueous solution of
sodium bicarbonate. The solution was evaporated and extracted into
chloroform. The chloroform layer was then filtered. The chloroform layer
contained a mixture of malathion, mono-methyl malathion and dimethyl
malathion. Dimethyl malathion was isolated by preparative HPLC.

(g) Methyl Malathion

##STR00009##

[0266] Mono-methyl malathion was isolated by preparative HPLC from the
reaction mixture described in (f).

[0272] The chemical was prepared by two chemical steps and one
purification step.

(i) Step I: Preparation of Dithiolo Acids

[0273] Twenty grams of P2S5 was suspended in toluene. A mixture
of 1:1 (v/v) of methanol:ethanol was added drop-wise while maintaining
the temperature below 70° C. After addition of the
methanol:ethanol, air was bubbled through the reaction mass to remove any
dissolved H2S. The mixture was then cooled to ambient temperature
and any un-reacted P2S5 removed by filtration. The toluene
solution was extracted with water.

(ii) Step II: Preparation of Crude Malathion Derivatives

[0274] The aqueous layer containing the dithiolo acids was treated with
diethyl maleate together with hydroquinone at 55° C. After 5
hours, the reaction mass was cooled to ambient temperature and the layers
separated. The lower organic layer was washed twice with water and the
reaction mixture analyzed by gas chromatography and HPLC. There were
three main products: (i) malathion (19.3%); (ii) O,O-methyl ethyl
S-(1,2-dicarboethoxy)ethyl phosphorodithioate (38.82%); and, (iii)
O,O-diethyl S-(1,2-dicarboethoxy)ethyl phosphorodithioate (8.87%) (data
is shown as the % area).

[0276] The corresponding mercapto diacid (10 grams) was esterified in 100
ml of absolute ethanol in the presence of 1 gram of sulfuric acid 98% at
reflux for 3 hours. The reaction mixture was then cooled to ambient
temperature and a major portion of the ethanol removed under reduced
pressure. Water and ethylacetate were added to the residue. The layers
were separated and the organic solvent removed to yield a colorless
product with a purity by gas chromatography of 96% (w/w).

(l) Tetraethyl dithiosuccinate

[0277] Diethyl 2-mercaptosuccinate was treated with 30% (v/v) hydrogen
peroxide at ambient temperature for 16 hours in the presence of catalytic
amount of HCl (32%). The reaction mixture was extracted with ethyl
acetate and the organic layer washed with 2% sodium hydroxide solution in
water to get rid of any un-reacted starting material. Removal of the
solvent yielded a colorless product with purity of 95% (GC).

(m) Tetraethyl thiosuccinate

[0278] The sodium salt of diethyl 2-mercaptosuccinate was reacted in two
layer system (toluene/water) at ambient temperature with diethyl malaeate
to yield the desired product.

Example 11

Additional Purification of the Malathion Prepared in Example 3

[0279] The malathion from Example 3 was further purified as follows. The
malathion was stirred with water (approximately 1:3 parts by weight) and
the mixture heated to about 65° C. under vacuum. Fresh water was
added and the mixture distilled a second time. After distillation of
about 35 liters of water, the purity of the malathion was checked by
HPLC.

Example 12

Analysis of Malathion from Example 11

[0280] The purity of the malathion and the percentage of impurities
present were determined by HPLC. The mobile phase composition and/or flow
rate were adjusted to meet the chromatographic parameters. The results of
the HPLC analysis for one batch of wet malathion is shown below in Table
VIII. Malathion free of water may be obtained by heating the malathion
after addition of water followed by azeotropic distillation at a
temperature from about 35° C. to about 45° C., together
with air bubbling through the wet mass. The water content may be
monitored by the Karl Fisher procedure. United States Pharmacopeia
<921>. When the water content is reduced to not more than 0.1%
(w/w), the malathion is cooled and filtered to remove any foreign
particles. Filtration may be through glass paper.

[0281] The aqueous solution of dimethyldithiophosphoric acid prepared in
Example 1 was combined with diethyl maleate (1.33 kg) and hydroquinone
(3.3 g), and the resulting two-phase mixture was heated for 8 h at
53-57° C. under nitrogen atmosphere. The two-phase mixture was
cooled to 22-30° C., and the phases were separated. The organic
phase was washed with water (2×1 kg) to afford crude malathion
(1.86 kg) containing at least about 30% (w/w) diethyl fumarate.

Example 14

Removal of Diethyl Fumarate from Crude Malathion Under Acidic Conditions

[0282] Sodium bisulfite (1 kg) was dissolved in water (4.kg), and the pH
of the solution was adjusted to 6.1-6.3 by addition of 50% (w/w) sodium
hydroxide (0.37 kg).

[0283] The pH-adjusted solution was combined with the crude malathion from
Example 13, and the resulting two-phase mixture was heated at
60-65° C. for 2 hours. The final pH of the mixture was about
6.8-6.9. The mixture was cooled to 22-30° C. and the phases were
separated. The organic phase was washed with water (1.5 kg), and the
phases were separated. Next, the organic phase was washed with 2.5% (w/w)
aqueous sodium hydroxide (1.5 kg), and the phases were separated.
Finally, the organic phase was washed with water (2×1 kg) to afford
malathion (0.94 kg).

[0284] The purity of the obtained malathion was determined using HPLC as
set forth above (See Methodology and Protocols, In-Process Purity
Determination by HPLC). The quantities of known and unknown impurities
are listed in the following table:

[0285] These data demonstrate that greater than 99% (w/w) of the diethyl
fumarate was removed from the crude malathion. These data further
demonstrate that the purified malathion contained only 0.04% (w/w) of
tetraethyl dithiodisuccinate.

Example 15

Removal of MeOOSPS from Crude Malathion

[0286] Water (2.8 kg) was added to the malathion from Example 14, and the
resulting two-phase mixture was subjected to azeotropic distillation over
the course of four days at a temperature of about 35-50° C. and a
pressure of about 30-60 mbar. Water was added to the mixture at
approximately one-hour intervals to replace the quantity removed by
distillation during that period (about 0.2-0.7 L each time). A total of
about 34.2 L of water was distilled during this process. The two-phase
mixture was cooled to 22-30° C., and the phases were separated,
providing wet pharmaceutical grade malathion (0.84 kg).

[0287] The purity of the obtained malathion was determined using HPLC as
set forth above (See Methodology and Protocols, In-Process Purity
Determination by HPLC). The quantities of known and unknown impurities
are listed in the following table:

[0288] These data demonstrate that at least 97% (w/w) of the MeOOSPS was
removed from the malathion of Example 3. These data further demonstrate
that the purified malathion contained only 0.07% (w/w) of isomalathion.

Example 16

Preparation of Dry Pharmaceutical Grade Malathion

[0289] The wet pharmaceutical grade malathion from Example 15 was heated
at 38-42° C., and air was bubbled through the wet mass for about
20 hours. Water content was then determined by a Karl Fisher procedure
according to USP Method I <921>, and found to be 0.05% (w/w). The
mixture was then cooled to room temperature and filtered through glass
paper, to provide dry pharmaceutical grade malathion (0.8 kg).

[0290] The purity of the obtained malathion was determined using HPLC as
set forth above (See Methodology and Protocols: End-of-Process
Determination of Assay, Purity, and Impurities Other Than Isomalathion,
End-of-Process Determination of Isomalathion). The quantities of known
and unknown impurities are listed in the following table:

[0291] The assay of the obtained malathion was determined using HPLC as
set forth above (See Methodology and Protocols: End-of-Process
Determination of Assay, Purity, and Impurities Other Than Isomalathion),
and found to be 99.5% (w/w).

Example 17

Preparation of Pharmaceutical Grade Malathion

[0292] Two additional batches of pharmaceutical grade malathion were
prepared by procedures analogous to those in Examples 1 and 13-16. The
purity of the obtained malathion was determined using HPLC as set forth
above (See Methodology and Protocols: End-of-Process Determination of
Assay, Purity, and Impurities Other Than Isomalathion, End-of-Process
Determination of Isomalathion). The quantities of known and unknown
impurities are listed in the following table:

[0293] Four (4) samples of Dry Pharmaceutical Grade Malathion from Example
16, each weighing about 3-3.5 grams, were placed in separate clear glass
bottles closed by a cap coated with polytetrafluoroethylene (PTFE). Each
bottle was then inserted into a separate black polyethylene (PE) bag,
which was tightly closed with a strip fastener. Each bag was then placed
in a separate carton box.

[0294] The four (4) samples were stored for three (3) months under the
following conditions:

[0295] The purity of each sample was determined after storage for one (1),
two (2), and three (3) months using HPLC as set forth above (See
Methodology and Protocols: End-of-Process Determination of Assay, Purity,
and Impurities Other Than Isomalathion, End-of-Process Determination of
Isomalathion). The quantities of known and unknown impurities for each
sample are listed in the following tables:

[0296] This Example demonstrates that the pharmaceutical grade malathion
prepared in accordance with the present invention is storage stable.

Comparative Example 1

Purification of Malathion Contaminated with Diethyl Fumarate at Alkaline
pH

[0297] Crude malathion was prepared as in Examples 1 and 13, and then
treated with sodium bisulfite as in Example 14. However, the final pH of
the two-phase mixture was about 7.2.

[0298] The purity of the obtained malathion was determined using HPLC as
set forth above (See Methodology and Protocols, In-Process Purity
Determination by HPLC). The quantity of tetraethyl dithiodisuccinate was
0.24% (w/w).

[0299] This Example demonstrates that when the pH of the mixture rose
above 7, the tetraethyl dithiodisuccinate level was greater than 0.2%
(w/w).

Comparative Example 2

Dimerization of Diethyl 2-Mercaptosuccinate at Alkaline pH

[0300] Sodium bisulfite (20 g, 0.192 mol) was dissolved in water (80 mL),
and the pH of the solution was adjusted to 7.46 by addition of 50% (w/w)
sodium hydroxide (15.37 g, 0.192 mol).

[0301] The pH-adjusted solution (4 g) was combined with diethyl
2-mercaptosuccinate (0.5 g), and the resulting mixture was stirred at
ambient temperature. The quantity of tetraethyl dithiodisuccinate was
determined at various time points by gas chromatography as set forth
above (See Methodology and Protocols, Malathion Analysis by GC).

[0303] Three (3) commercial batches of pharmaceutical grade malathion were
obtained. The three (3) batches of pharmaceutical grade malathion were
prepared and purified by a process different from the process of the
present invention. The purity of each commercial batch of malathion was
determined using HPLC as set forth above (See Methodology and Protocols:
End-of-Process Determination of Assay, Purity, and Impurities Other Than
Isomalathion, End-of-Process Determination of Isomalathion). The
quantities of known and unknown impurities are listed in the following
table:

[0304] Numerous references, including patents and various publications,
are cited and discussed in the description of this invention. The
citation and discussion of such references is provided merely to clarify
the description of the present invention and is not an admission that any
reference is prior art to the invention described herein. All references
cited and discussed in this specification are incorporated herein by
reference in their entirety. The embodiments illustrated and discussed in
this specification are intended only to teach those skilled in the art
the best way known to the inventors to make and use the invention.
Nothing in this specification should be considered as limiting the scope
of the present invention. Modifications and variation of the
above-described embodiments of the invention are possible without
departing from the invention, as appreciated by those skilled in the art
in light of the above teachings. It is therefore understood that, within
the scope of the claims and their equivalents, the invention may be
practiced otherwise than as specifically described.